This project will build on the large amount of important data generated by projects 1-5 to develop a computational model of the HIV infection and host response interactions in order to study the effectiveness of the host immune response and develop therapeutic and preventative therapeutic strategies based on innate immunity. The Pis have pioneered iterative modeling and experimental studies in the two relevant complementary topics: the host inflammatory and innate immune response (Hoffmann) and HIV genetic programs and fate decision making (Weinberger). The proposed project is closely integrated into the purely experimental as well as genetic and bioinformatics projects ofthe Program; however, by focusing on mechanistic modeling, the project 6 will not merely function as a repository of results and mechanisms, but yield additional and significant insights. Here, we will first (Aim 1) leverage existing expertise in TLR signaling networks (Hoffmann), build on data from collaborative projects, as well as some key measurements in our own lab to construct a model for the host response network. Next (Aim 2) we will leverage existing expertise in HIV gene circuit (Weinberger), build on data from collaborative projects, as well as some key measurements in our own lab to construct a model for the HIV infection mechanism. We will then integrate the models for HIV infection and host responses focusing on HIV resistance factors as well as viral accessory proteins manipulating host response signaling. Finally (Aim 3), we will apply the model to identify critical mechanisms and opportunities for therapeutic intervention, characterize the mechanistic roles of SNPs associated with elite-suppressor, and contrast dendritic cells in different microenvironments and exposure histories and T-lymphocytes. In addition (Aim 4), we will develop web-based user interfaces to facilitate integration of computational simulations into experimental analysis within the Program as well as the broader HIV research community.